PROJECT SUMMARY While the value of identifying individuals in the population who carry `actionable' variants and screening their relatives (i.e. cascade screening) is widely acknowledged, there are numerous barriers in implementing this process and studying the optimal approaches for doing this. First, the feasibility of returning genetic results is complex as it depends on many issues, including the community expectations, consent form language, local IRB considerations, and logistical, feasibility, and cost issues, among others. Second, even in very large population studies, the frequency of `actionable' variants is typically so low that it is difficult to study optimal approaches for dissemination of results and screening of family members in any systematic way. We have identified 124 Amish individuals in Lancaster County, PA, harboring a mutation in KCNQ1 that is associated with long QT syndrome type 1 (LQT1), a trait linked to arrhythmia-associated sudden death. KCNQ1 is regarded by the American College of Medical Genetics (ACMG) as `actionable' since appropriate preventative treatment is available (beta-blockers). This mutation (p.Thr224Met; rs199472706) is highly enriched in the Amish community due to a founder effect. We are proposing a mixed methods study that will implement a quantitative intervention aimed at improving uptake of cascade screening and qualitative interviews aimed at gaining insights into: the impact of the return of results process, why participants choose or choose not to initiate cascade screening of family members, and how the intervention impacts their decisions. In Aim 1 we will implement a simplified cascade screening intervention that offers free, mail-in, saliva-based testing of family members. The primary outcome is the rate of uptake of cascade screening before versus after the implementation of the simplified screening intervention. The secondary outcomes are the rate of disclosure to family members before versus after, the proportion of informed family members who get screened before versus after, and the uptake of clinical recommendations. In Aim 2 we will perform in-depth interviews of 30 probands and 45 family members to assess: understanding of genetic test results and cascade screening, how decisions are made regarding pursuing or not pursuing cascade screening, and predisposing, enabling, and need-based themes that influence uptake of cascade screening. This population provides a unique and powerful opportunity to evaluate and formulate strategies for returning genetic results to individuals discovered to have `actionable' genetic variants and enhancing screening of their family members.